Method for preparing substituted benzyl bromides

ABSTRACT

Substituted benzyl bromides of the formula I ##STR1## where at least one substituent R 1-5  is an electron-attracting group such as fluorine, chlorine, bromine, C 1  -C 4  -alkoxycarbonyl, cyano or nitro, and the other substituents R 1-5  are hydrogen or methyl, 
     are prepared by bromination of substituted toluenes of the formula II ##STR2## with a brominating agent at from 20 to 95° C.

This Application is a 371 of PCT/EP98/04485 filed Jul. 20, 1998.

The present invention relates to a process for preparing substitutedbenzyl bromides of the formula I ##STR3## where at least one substituentR¹⁻⁵ is an electron-attracting group such as fluorine, chlorine,bromine, C₁ -C₄ -alkoxycarbonyl, cyano or nitro, and the othersubstituents R¹⁻⁵ are hydrogen or methyl,

by bromination of substituted toluenes of the formula II ##STR4## with abrominating agent at from 20 to 95° C.

Side-chain bromination of alkylaromatic compounds has been known for along time (Houben-Weyl, Volume 5/4, pages. 331 et seq. (1960)).

It is pointed out in this review that electron-attracting substituents,such as halogen atoms or nitro groups, make this reaction difficult.Compounds which can be substituted only with great difficulty,specifically nitrotoluenes, can often be induced to react only attemperatures above 100° C. and under pressure, which involvesconsiderable safety problems because of the low thermal stability of thecompounds.

There is a description in more recent literature (EP-A 336 567) of theparticularly difficult preparation of o-nitrobenzyl bromide bybromination of o-nitrotoluene with hydrogen bromide in the presence ofhydrogen peroxide while irradiating with light, it having been possibleto obtain selectivities of more than 90%. This process has been found tohave the following disadvantages:

The bromine free radicals which are required are generated byirradiating with light which, on continuous operation, may result incoating of the lamps and thus considerable adverse effects.

Achieving the optimum depends on maintaining the narrow temperaturerange of 60-70° C. Good selectivities are obtained only with relativelylow conversions.

For optimal reaction conditions, the hydrogen peroxide/substrate molarratio and the hydrogen peroxide/hydrogen bromide molar ratio can bevaried only within relatively narrow limits.

It has now been found that benzyl bromides substituted byelectron-attracting groups are obtained with very good selectivitieswhen the bromination is carried out in the presence of an azocarbonitrile or of an azo carboxylic ester and in the presence of anoxidizing agent.

It is surprising that it is possible to generate bromine free radicalsusing organic initiators even in the presence of strong oxidizingagents. Azo carboxylic esters and azo carbonitriles are particularlystable in the presence of said oxidizing agents and are thereforepredestined for use as initiators in the novel process. The novelprocess has a number of industrial and economic advantages which arebriefly listed below and are explained in detail hereinafter:

1. Omission of the elaborate apparatus needed for the irradiation

2. Possibility of wide variation of the brominating and oxidizing agentsused

3. Temperature window wider and extending to lower reaction temperatures

4. The sequence of the addition of the individual reactants can bereversed. The brominating agent is metered into a mixture of thesubstrate to be brominated and the oxidizing agent. The concentration ofcorrosive brominating agent, especially hydrogen bromide, in thereaction vessel can be kept very low in this way.

Solvents suitable for the novel process are those which are inert duringthe bromination, for example aromatic hydrocarbons such as benzene,tert-butylbenzene and tert-amylbenzene, halogenated hydrocarbons such asmethylene chloride, chloroform and chlorobenzene, 1,2-dichloroethane,tetrachloromethane, dichlorobenzene or trichlorobenzene. It is alsopossible to use mixtures of said solvents.

Halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane,chloroform, tetrachloromethane, ortho- or para-dichlorobenzene,1,2,4-trichlorobenzene and, in particular, chlorobenzene are preferred.

The ortho-nitrotoluenes II employed in the novel process can in mostcases be purchased or are easily obtainable by processes described inthe literature (eg. Organikum, Barth Verlagsgesellschaft (1993) 320 etseq.).

In contrast with the disclosure in EP-A 336 567, the procedure for thenovel process is very flexible. It is possible to employ brominatingagents such as elemental bromine, or bromine salts such as sodiumbromide inter alia, and hydrogen bromide, preferably in the form of itsaqueous solution, hydrobromic acid. Industrial azeotropic mixturescontaining hydrobromic acid are particularly preferred.

Examples of oxidizing agents suitable for oxidizing the hydrogen bromideor the bromide ions are peracids, peroxides, hypochlorite (chlorinebleaching solution), chlorine, sodium bromate and potassiumperoxodisulfate, and hydrogen peroxide is particularly suitable.

In a preferred embodiment of the novel process, the amounts of oxidizingagents used are such that the hydrogen bromide formed in the reaction isalso reoxidized. From 1.5 to 2.0 equivalents of the oxidizing agent arepreferably added per bromide equivalent. If, on the other hand,elemental bromine is used as source of bromine, it is sufficient to addfrom 0.5 to 1.0 equivalent (based on bromine) of an oxidizing agent. Itis possible in this way almost to halve the amount of brominating agentemployed.

The brominating agent is generally employed in a molar ratio of 0.7-1.3,and preferably in a molar ratio of 0.9-1.0, relative to theo-nitrotoluene II.

A particular advantage of the novel process is that azo compounds suchas azo carboxylic esters and azo carbonitriles are used as initiators,and thus irradiation with light can be omitted. These initiators can bedissolved without difficulty in the precursor or in the solvent andaccordingly can be present from the outset or metered in. Theparticularly preferred azo compound is azoisobutyronitrile (AIBN).

The initiators are generally added in a concentration of from 0.1 to 20mol %, based on the bromine or bromide ion concentration (depending onstarting material), and preferably in a concentration of from 1 to 10mol %, to the reaction mixture.

The bromination is carried out at from 20 to 100° C., preferably 20 to80° C. The optimal reaction temperature depends, on the one hand, on thethermal stability of the o-nitrotoluene II and the product III obtainedtherefrom and, on the other hand, on the initiator decompositiontemperature. The following table gives a review of various initiatorswith their structures and 10 h half-life decomposition temperatures. Thereaction is preferably carried out slightly above or below the 10 hhalf-life decomposition temperature of the initiator (±10° C.).Operating below the 10 h half-life decomposition temperature generallyresults in sparing use of initiator and higher selectivity. However,this result is at the expense of longer reaction times. It is thuspossible, by choosing a suitable initiator, for the reaction temperatureto be varied within wide limits and adjusted to be optimal for theparticular conditions.

                                      TABLE                                       __________________________________________________________________________                                             10 h Half-life                         Designa-   decomposition                                                      tion Name Structure temperature                                             __________________________________________________________________________      A 2,2'-Azobis(4-methoxy-  2,4-dimethylvalero-  nitrile)                                                                30° C.                         - B 2,2'-Azobis(2-cyclo-  propylpropionitrile)                                                                        42° C.                         - C 2,2'-Azobis(2,4-  dimethylvaleronitrile)                                                                          51° C.                         - D 2,2'-Azobis(2-methyl-  propionitrile)                                                                             65° C.                         - E Dimethyl 2',2'-  azobis(2-methyl-  propionate)                                                                    66° C.                         - F 2,2'-Azobis(2-methyl-  butyronitrile)                                                                             67° C.                         - G 1,1'-Azobis(cyclo-  hexane-1-carbonitrile)                                                                        88° C.                      __________________________________________________________________________

As is evident from the table, it is perfectly possible to preparesensitive compounds which easily decompose by the novel process at mildtemperatures in the range from 20 to 50° C., it being necessary toaccept somewhat longer reaction times, but it being possible toeliminate the safety risk of an exothermic decomposition. It issurprising that the results obtained with organic peroxides asinitiators are worse throughout, whereas very good results are obtainedby the novel process with azo compounds in the presence of oxidizingagents. It may be advantageous in some cases to add a mineral acid,specifically H₂ SO₄.

The bromination is preferably carried out in a two-phase system. Thetwo-phase system generally comprises the solution of the bromine salt inwater or, preferably, the hydrobromic acid together with the solventand, where appropriate, the initiator or a part-quantity of theinitiator. The mixture is brought to the reaction temperature and thenthe toluene derivative II is metered in, in the presence or absence ofthe initiator, continuously or in portions over the course of from ahalf to several hours. The oxidizing agent is metered in parallel withthe metering of II generally in such a way that no excess bromine ispresent in the reaction mixture. It is likewise possible to mix thesubstrate II with the brominating agent and the initiator and to controlthe reaction by the metering in of the oxidizing agent.

When bromine is used as source of bromine, the procedure is generallysimilar to that described above but bromine is metered into water andsolvent, with or without initiator. In this procedure, the substrate IIcan be present from the outset or metered in.

When stable oxidizing agents are used, they can be mixed with thesubstrate II, and the course of the reaction can be controlled by theaddition of the bromine component. When hydrogen peroxide is employed,the latter procedure is generally possible at up to 50° C.

The bromination can be carried out batchwise or, preferably,continuously. The continuous procedure has the advantage that theapparatus is of smaller dimensions and thus the amount of solutionscontaining the substrate II kept at elevated temperature is less. Thepronounced thermal instability of some toluene derivatives II thus meansthat the continuous process is advantageous in terms of industrialsafety.

After the metering in is complete, the reaction mixture is usually keptat the chosen reaction temperature for from 0.5 to 3 hours. Thermallystable benzyl bromides are, as a rule, purified by distillation, whilethermally unstable benzyl bromides are further processed in the solutionobtained from the novel process.

The novel process is presented by means of examples below:

EXAMPLE 1

Preparation of o-nitrobenzyl bromide

a) A solution of 6.6 g (1 mol % based on the hydrobromic acid) ofazoisobutyronitrile (AIBN) in 1350 g of chlorobenzene were mixed with620 g (3.6 mol) of 47% strength hydrobromic acid in a 2.5 liter flatflange flask with impeller stirrer (300 rpm) and baffle. The contents ofthe reactor were heated to 75° C. After this temperature was reached,feeds I and II were fed in by two metering pumps.

Feed I: A solution of 26.2 g (4 mol %) of AIBN in 548 g (4.0 mol) ofortho-nitrotoluene was introduced continuously over two hours;

Feed II: 725 g (3.2 mol) of 15% strength H₂ O₂ were introduced in such away that no excess bromine was present in the solution. About 2.5 hourswere required for this.

Stirring was continued at 75° C. for 2 hours after completion of thefeeding in, the stirrer was then switched off and the phases wereseparated at 75° C. 2146.4 g of organic phase were obtained with thefollowing composition (solvent not included):

    ______________________________________                                        60.4%            o-nitrobenzyl bromide                                          21.5% o-nitrotoluene                                                          18.2% o-nitrobenzal bromide                                                 ______________________________________                                    

Yield of o-nitrobenzyl bromide: 58.1% based on o-nitrotoluene.

b) 25 g of chlorobenzene in which 13.7 g of o-nitrotoluene and 0.72 g of2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile) were dissolved weremixed with 0.24 g of conc. H₂ SO₄ and 7.8 g of 50% strength H₂ O₂ at 27°C. in a 250 ml stirred apparatus. While stirring vigorously, 19.7 g of47% strength hydrobromic acid were added dropwise at 25-27° C. over thecourse of about 8 hours, stopping the addition of hydrobromic acid ifmuch bromine was released (brown color) and stirring at the reactiontemperature until decolorization occurred. GC analysis of the org.phase:

    ______________________________________                                        72.7%            o-nitrotoluene                                                 23.9% o-nitrobenzyl bromide                                                    0.3% o-nitrobenzal bromide                                                 ______________________________________                                    

c) 13.7 g (0.1 mol) of o-nitrotoluene, 25 g of chlorobenzene, 600 mg(2.7 mmol) of V 65 (supplied by Wako;2,2'-azobis(2,4-dimethylvaleronitrile)), 300 mg of H₂ SO₄ and 16.4 g(0.15 mol) of 30% strength H₂ O₂ were mixed at 45° C. 10 g of 47%strength hydrobromic acid were added dropwise over the course of 75 min,and the mixture was stirred at 45° C. for a further 75 min. A further 5g of hydrobromic acid were added, and the mixture was stirred at roomtemperature for 12 h. Then 3 g of hydrobromic acid and, in two portions,5 g and then a further 10 g of a solution of chlorobenzene and V 65(total 15 g of chlorobenzene +0.86 g (3.9 mmol) of V 65) were added.

Qualitative [sic] HPLC of the org. phase:

    ______________________________________                                        56.9%            o-nitrobenzyl bromide                                          38.4% o-nitrotoluene                                                           4.7% o-nitrobenzal bromide                                                 ______________________________________                                    

d) 13.7 g of o-nitrotoluene, 25 g of chlorobenzene, 0.58 g of2,2'-azobis(2,4-dimethylvaleronitrile), 0.24 g of conc. H₂ SO₄ and 19 gof 47% strength hydrobromic acid were mixed in a 250 ml stirredapparatus and, while stirring vigorously, 60 g of 10% strength aqueoushydrogen peroxide solution were added dropwise over the course of 13hours. During this, 1 ml portions of a solution consisting of 0.58 g of2,2'-azobis(2,4-dimethylvaleronitrile) in 10 g of chlorobenzene wereadded at intervals of one hour to the reaction mixture. The reaction wasstopped after 13 hours. GC analysis of the org. phase:

    ______________________________________                                        43.9%            o-nitrotoluene                                                 44.2% o-nitrobenzyl bromide                                                    1.3% o-nitrobenzal bromide                                                 ______________________________________                                    

e) 13.7 g of o-nitrotoluene, 35 g of chlorobenzene, 0.24 g of conc. H₂SO₄, 1.74 g of 2,2'-azobis(2,4-dimethylvaleronitrile) and 8.8 g of 30%strength aqueous hydrogen peroxide solution were mixed at 45° C. in a250 ml stirred apparatus and, while stirring vigorously, 6.6 g ofbromine were added dropwise over a period of 24 hours at a rate suchthat decolorization of the brown solution took place. GC analysis of theorg. phase:

    ______________________________________                                        52.6%            o-nitrotoluene                                                 38.4% o-nitrobenzyl bromide                                                    0.9% o-nitrobenzal bromide                                                 ______________________________________                                    

f) 13.7 g of o-nitrotoluene, 38.8 g of chlorobenzene, 0.24 g of conc. H₂SO₄ and 19.8 g of 47% strength hydrobromic acid were mixed at 62° C. ina 250 ml stirred apparatus, 2.15 g of 2,2'-azobis(2-methylpropionitrile)were added and, while stirring vigorously, 40 g of chlorine bleachingsolution (12.5% active chlorine) were slowly added dropwise over aperiod of 25 hours.

GC analysis of the org. phase

    ______________________________________                                        37.4%            o-nitrotoluene                                                 44.4% o-nitrobenzyl bromide                                                    2.3% o-nitrobenzal bromide                                                 ______________________________________                                    

g) 13.7 g of o-nitrotoluene, 38.8 g of chlorobenzene, 0.24 g of conc. H₂SO₄, 19.8 g of 47% strength aqueous hydrobromic acid and 0.72 g of2,2'-azobis(2-methylpropionitrile) were mixed at 61° C. in a 250 mlstirred apparatus. At this temperature, a solution of 3.27 g of sodiumbromate (NaBrO₃) in 23 ml of water was added dropwise over the course of15 hours. GC analysis of the org. phase:

    ______________________________________                                        45.7%            o-nitrotoluene                                                 44.8% o-nitrobenzyl bromide                                                    1.6% o-nitrobenzal bromide                                                 ______________________________________                                    

h) The procedure was as in Example g but at 62-63° C., and instead ofNaBrO₃ a solution of 17.5 g of potassium peroxodisulfate in 50 ml ofwater was added to the reaction mixture as oxidizing agent. Workup tookplace after 20 h. GC analysis of the org. phase:

    ______________________________________                                        36.5%            o-nitrotoluene                                                 51.6% o-nitrobenzyl bromide                                                    2.7% o-nitrobenzal bromide                                                 ______________________________________                                    

i) A solution of 137 g of o-nitrotoluene in 800 ml of chlorobenzene anda solution of 103 g of sodium bromide, 6 g of Na₂ HPO₄ in 1 1 of waterwere mixed together with 2.5 g of conc. H₂ SO₄ and 20 g of2,2'-azobis(2-methylpropionitrile) at 65° C. This two-phase mixture wasstirred vigorously while 64 g of chlorine gas (Cl₂) were passed in overthe course of 2 hours. GC analysis of the org. phase:

    ______________________________________                                        34%              o-nitrotoluene                                                 50% o-nitrobenzyl bromide                                                      4% o-nitrobenzal bromide                                                   ______________________________________                                    

j) 13.7 g of o-nitrotoluene, 38.8 g of chlorobenzene, 0.24 g of conc. H₂SO₄ and 19.8 g of 47% strength aqueous hydrobromic acid were mixed at62° C. in a 250 ml stirred apparatus, 2.32 g of2,2'-azobis(2-methylpropionitrile) were added and, while stirringvigorously, 11.6 g of peroxyacetic acid (32% strength) were addeddropwise in small portions over the course of 25.5 hours.

GC analysis of the org. phase:

    ______________________________________                                        53.5%            o-nitrotoluene                                                 32.2% o-nitrobenzyl bromide                                                    0.5% o-nitrobenzal bromide                                                 ______________________________________                                    

EXAMPLE 2

Preparation of 3-chloro-2-bromobenzyl bromide

267.7 g of 2-bromo-3-chlorotoluene, 530 g of chlorobenzene, 2.5 g ofconc. H₂ SO₄, 257.9 g of 47% strength hydrobromic acid and 14 g of2,2'-azobis(2-methylpropionitrile) were mixed at 63° C. in a 2 l stirredapparatus. 332.3 g of a 10% strength aqueous hydrogen peroxide solutionwere added dropwise over the course of one hour and 25 minutes, and thenthe mixture was stirred at 63° C. for 30 minutes. GC analysis of theorg. phase:

    ______________________________________                                        32.2%         3-chloro-2-bromotoluene                                           56.5% 3-chloro-2-bromobenzyl bromide                                           4.2% 3-chloro-2-bromobenzal bromide                                        ______________________________________                                    

These 3 components could be separated and purified by distillationwithout difficulty.

EXAMPLE 3

Preparation of 3-methyl-2-bromobenzyl bromide

104.5 g of 2-bromo-m-xylene(2,6-dimethylbromobenzene), 200 g ofchlorobenzene, 1 g of conc. H₂ SO₄, 87.2 g of 47% strength hydrobromicacid and 6 g of 2,2'-azobis(2-methylpropionitrile) were mixed at 63° C.in a 1 1 stirred apparatus. 75 g of 10% strength aqueous hydrogenperoxide solution were added dropwise over the course of 30 minutes, andthe mixture was stirred at 64° C. for 25 minutes.

    ______________________________________                                        40.7%        2,6-dimethylbromobenzene                                           45.8% 3-methyl-2-bromobenzyl bromide                                           0.6% 3-methyl-2-bromobenzal bromide                                           3.0% 2,6-bis-(bromomethyl)bromobenzene                                     ______________________________________                                    

Once again, the benzyl bromide component could be removed and obtainedin pure form by distillation.

EXAMPLE 4

Preparation of 4-chloro-2-fluorobenzyl bromide

361.5 g of 4-chloro-2-fluorotoluene, 520 g of chlorobenzene, 6 g ofconc. H₂ SO₄, 467 g of 47% strength hydrobromic acid and 2.7 g of2,2'-azobis(2-methylpropionitrile) were mixed at 70° C. in a 4 l stirredapparatus. 620.5 g of a 10% strength aqueous hydrogen peroxide solutionand a solution of 16.5 g of 2,2'-azobis(2-methylpropionitrile) in 270 gof chlorobenzene were simultaneously added dropwise over the course of1.5 hours. The mixture was then stirred at 70° C. for 1 hour. GCanalysis of the org. phase:

    ______________________________________                                        31.2%          4-chloro-2-fluorotoluene                                         60.5% 4-chloro-2-fluorobenzyl bromide                                          4.3% 4-chloro-2-fluorobenzal bromide                                       ______________________________________                                    

In this case too, purification was possible by fractional distillation.

EXAMPLE 5

Preparation of methyl 2,4-dichloro-3-(bromomethyl)benzoate

94.6 g of methyl 2,4-dichloro-3-methylbenzoate, 315 g of chlorobenzene,1 g of conc. H₂ SO₄, 85.5 g of 47% strength hydrobromic acid and 3.5 gof 2,2'-azobis(2-methylpropionitrile) were mixed at 63° C. in a 1 1stirred apparatus. Then, at temperatures from 63 to 68° C., 73.5 g of10% strength aqueous hydrogen peroxide solution were added over thecourse of 35 minutes. The mixture was stirred at the reactiontemperature for 2 hours and then a further 73.5 g of 10% strengthhydrogen peroxide solution were added dropwise over the course of 30minutes, a further 1.5 g of 2,2'-azobis(2-methylpropionitrile) wereadded to the reaction, the mixture was stirred at the reactiontemperature for 2 hours and 35 minutes, and finally 36.8 g of 10%strength hydrogen peroxide solution were added dropwise at 63-67° C.over the course of 15 minutes, the mixture was stirred at the reactiontemperature for a further 2 hours and cooled to room temperature, andthe organic phase was separated off. The chlorobenzene solutioncontained the required product methyl 2,4-dichloro-3-bromomethylbenzoatein a purity of 96.1% (according to HPLC analysis ignoring solvent).

We claim:
 1. A process for preparing substituted benzyl bromides of theformula I ##STR12## where at least one substituent R¹⁻⁵ is anelectron-attracting group comprising fluorine, chlorine, bromine, C₁ -C₄-alkoxycarbonyl, cyano or nitro, and the other substituents R¹⁻⁵ arehydrogen or methyl, by bromination of substituted toluenes of theformula II ##STR13## with a brominating agent selected from the groupconsisting of: bromine, bromine salts and hydrogen bromide, optionallyin the form of its aqueous solution, at from 20 to 95° C., wherein thebromination is carried out in the presence of an azo carbonitrile or ofan azo carboxylic ester and in the presence of an oxidizing agent.
 2. Aprocess as claimed in claim 1, wherein from 0.5 to 1 equivalent of anoxidizing agent is employed in the case of elemental bromine asbrominating agent, and from 1.5 to 2 equivalents of an oxidizing agentare employed in the case of bromides or hydrogen bromide.
 3. A processas claimed in claim 1, wherein hydrogen peroxide, peracetic acid,chlorine, sodium hypochlorite, sodium bromate or potassiumperoxydisulfate are used as oxidizing agent.
 4. A process as claimed inclaim 1, wherein hydrogen peroxide is used as oxidizing agent and isinitially present together with the substrate to be brominated at up to50° C.
 5. A process as claimed in claim 1, wherein the bromination iscarried out in a two-phase system.
 6. A process as claimed in claim 1,wherein the bromination is carried out continuously.